Process for the preparation of deuterated ethanol from D2O

ABSTRACT

The invention relates to a process for the preparation of a deuterated ethanol from ethanol, D2O, a ruthenium catalyst, and a co-solvent.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of adeuterated ethanol from D₂O.

BACKGROUND OF THE INVENTION

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen.Deuterium-enriched organic compounds such as a deuterated ethanol areknown. U.S. Pat. No. 8,658,236 describes an alcoholic beverage of waterand ethanol, wherein at least 5 mole percent of the ethanol is adeuterated ethanol. This alcoholic beverage is believed to diminish thenegative side effects associated with the consumption of ethanol.

The production of a deuterated-ethanol containing alcoholic beveragerequires the preparation of a deuterated ethanol in an efficient, safe,and cost-effective manner. A known process for the preparation of adeuterated alcohol (e.g., deuterated ethanol) involves an H/D exchangereaction between a non-deuterated alcohol and D₂O. Depending on theprocess, the resulting deuterated alcohol may comprise deuterium indifferent positions. Examples of such processes can be found inChemistry Letters 34, No. 2 (2005), p. 192-193 “Ruthenium catalyzeddeuterium labelling of α-carbon in primary alcohol and primary/secondaryamine in D₂O”; Adv. Synth. Catal. 2008, 350, p. 2215-2218 “A method forthe regioselective deuteration of alcohols”; Org. Lett. 2015, 17, p.4794-4797 “Ruthenium Catalyzed Selective α- and α,β-Deuteration ofAlcohols Using D₂O” and Catalysis Communications 84 (2016) p. 67-70“Efficient deuterium labelling of alcohols in deuterated water catalyzedby ruthenium pincer complexes”.

Other routes to produce a deuterated alcohol involve several consecutivereactions requiring expensive and/or hazardous material. For each ofthese transformations, purification and isolation of the intermediatesare necessary.

In view of the above, it is desirable to be able to synthesizedeuterated ethanol in an efficient, safe and cost-effective manner. Itis further desirable to synthesize deuterated ethanol with deuterationsubstantially only at a desired position(s).

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a process for thepreparation of a deuterated ethanol from ethanol, D₂O, a rutheniumcatalyst, and a co-solvent.

These and other aspects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofa new process of making deuterated ethanol.

DETAILED DESCRIPTION OF THE INVENTION

It has now surprisingly been found that the combination of D₂O, aruthenium catalyst, and co-solvent allows for the effective andselective deuteration of ethanol.

Catalysis Communications 2016, 84, 67-70 (CC), mentions the deuterationof alcohol catalyzed by Ru-MACHO®-BH and Ru-MACHO®, but fails to mentionthe use of a co-solvent. Ru-MACHO®-BH was used only for the deuterationof 1-butanol and not ethanol. It has now been found that no deuterationof ethanol occurs when 1-butanol is replaced by ethanol in the systemdescribed in CC where the catalyst is Ru-MACHO®-BH.

CC also mentions the deuteration of ethanol catalyzed by Ru-MACHO® using20 mol % of NaOH. It has now been found that deuteration of ethanol isnot possible when NaOH is replaced by another base in the systemdescribed in CC where the catalyst is Ru-MACHO®. However, it hassurprisingly been discovered that the addition of a co-solvent todissolve the catalyst results in an efficient deuteration of ethanol, inparticular without the presence NaOH.

Thus, in an aspect, the present invention provides a novel process forthe preparation of a deuterated ethanol of formula (I):CR¹R²R³CR⁴R⁵OD   (I)

comprising: reacting ethanol and D₂O in the presence of a rutheniumcatalyst of formula (II) and a co-solvent:

whererin:

R¹-R⁵ are independently H or D, provided that the abundance of D in R⁴and R⁵ is at least 70%;

each R⁶ is independently selected from: H, a C₁₋₁₀ alkyl group, asubstituted C₁₋₁₀ alkyl group, a C₆₋₁₈ aromatic ring group, and asubstituted C₆₋₁₈ aromatic ring group;

each Ar is independently selected from a C₆₋₁₈ aromatic ring group and asubstituted C₆₋₁₈ aromatic ring group;

each n is independently 1 or 2;

L is a ligand;

X is a counterion; and,

the catalyst is soluble in the mixture of ethanol, D₂O, and theco-colvent.

In another aspect, the process is performed in the absence of a base.

In another aspect, the process is performed in the absence of NaOH.

The abundance of D in R⁴ and R⁵ (the CH₂ position) and in R¹, R², and R³(the CH₃ position) can be measured by ¹H NMR. The 70% abundance of D inR⁴ and R⁵ means that 70% of all R⁴ and R⁵ present are D (as opposed tothe natural abundance of 0.01%).

In another aspect, the abundance of D in R⁴ and R⁵ is at least 80%.Additional examples of the abundance of D in R⁴ and R⁵ include at least90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 99.5%.

In another aspect, the incorporation of D occurs preferentially in R⁴and R⁵ over R¹-R³. In another aspect, the abundance of D in R¹-R³ is atmost 50%. Additional examples of the abundance of D in R¹-R³ include atmost 45, 40, 35, 30, 25, 20, 15, 10, 5, and 1%.

In another aspect, the abundance of D in R⁴ and R⁵ is at least 90% andthe abundance of D in R¹-R³ is at most 5%. Additional examples include(a) at least 95% and at most 1%, and (b) at least 99% and at most 1%.

The conversion of ethanol to deuterated ethanol in the present processcan be determined by ¹H NMR. The conversion is the molar ratio ofdeuterated ethanol formed divided by the initial amount of startingethanol (un-enriched ethanol). In an aspect, the conversion percentage(molar ratio×100) is at least 90%. Additional examples of the conversionpercentage include at least 95%, at least 98%, and at least 99%. Theco-solvent forms a mixture together with ethanol and D₂O, whichsolubilizes the catalyst. Examples of co-solvents includetetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether(MTBE), diisopropyl ether, 1,2-dimethoxyethane, toluene (tol), benzene,xylenes, 1,4-dioxane, diglyme (diethylene glycol diethyl ether),cyclopentyl methyl ether (CPME), ethyl acetate, 1,2-dichloroethane,dimethylacetamide, dimethylformamide, and dimethyl sulfoxide.

The co-solvent may also be deuterated, wherein one or more H atoms ofthe co-solvent are replaced by D. Examples of deuterated co-solventsinclude d₈-tetrahydrofuran, d₈-toluene, and d₈-1,4-dioxane.

The reaction mixture may be monophasic or biphasic. For example, in thecase where the co-solvent is toluene or cyclopentyl methyl ether, themixture is biphasic.

For increasing the loading of the reactor and therefore theproductivity, the amount of the co-solvent is typically not too high.Thus, in another aspect, the volume ratio of D₂O to the co-solvent inthe reacting step is higher than 0.5. Additional examples of the volumeratio include from 1-30. Further examples of the volume ratio includefrom, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, to 30. The upperlimit for the volume ratio is typically about 30.

In another aspect, the molar ratio of D₂O to ethanol in the reactingstep is at least 3. Additional examples of the molar ratio include 3-10,3-75, and 3-100. Other examples of the molar ratio include at least 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, to 30. This leads to a higher Dincorporation at the desired position. The upper limit of the molarratio is typically or 75 or 100.

The ruthenium catalysts of formula (II) are known (see U.S. Pat. No.8,003,838, US2013/0303774, and US2016/0039853, which are incorporatedherein by reference).

Ligand “L” is any ligand suitable for the deuterium enrichment ofethanol in accordance with the presently claimed invention. In anotheraspect, the ligand is selected from: a monodentate ligand. Examples ofmonodentate ligands include phosphine (e.g., triphenylphosphine), carbonmonoxide, an olefin, water, acetonitrile, dimethylsulfoxide.

In another aspect, ligand L is carbon monoxide (CO).

In another aspect, counterion X is selected from:pentamethylcyclopentadienyl, chloride, bromide, iodide, hydride,triflate and BH₄.

In another aspect, one of the counterions X is hydride.

In another aspect, in formula (II) two vicinal R⁶ (except hydrogenatoms) may form a cyclic structure by covalent bond of carbon atomsthrough or without a nitrogen atom, an oxygen atom, or a sulfur atom.

In another aspect, in formula (II), each Ar is phenyl.

In another aspect, n is 1 (each P is bound to the N in the Ru complexvia a 2 carbon linker).

In another aspect, n is 2 (each P is bound to the N in the Ru complexvia a 3 carbon linker).

In another aspect, n=1 and all R⁶=hydrogen.

In another aspect, L is carbon monoxide and one of X is hydride.

In another aspect, the catalyst is a Ru complex of formula (III) (whichis commercially available asRu-MACHO®)({Bis[2-(diphenylphosphino)ethyl]amine}carboynlchlorohydridoruthenium(II)):

wherein Ph=phenyl.

In another aspect, the catalyst is the compound of formula (III) and thereaction is performed in the presence of an alkali metal borohydride.

Examples of alkali metal borohydrides include LiBH₄, NaBH₄, and KBH₄.

In another aspect, the catalyst is the compound of formula (III) and thereaction is performed in the presence of NaBH₄.

In another aspect, the catalyst is the compound of formula (III) and thereaction is performed in the presence of an alkali metal borohydride andin the absence of NaOH.

In another aspect, the catalyst is the compound of formula (III) and thereaction is performed in the presence of NaBH₄ and in the absence ofNaOH.

The combination of a suitable co-solvent and an alkali metal borohydrideusing the compound (III) was found to result high selectivity for the Dincorporation in R⁴-R⁵ over R¹-R³.

In another aspect, the catalyst is a Ru complex of formula (IV) (whichis commercially available as Ru-MACHO®-BH)(Carbonylhydrido(tetrahydroborato)[bis(2-diphenylphosphinoethyl)amino]ruthenium(II))):

wherein Ph=phenyl.

In another aspect, the catalyst is the compound of formula (IV) and thereaction is performed in the absence of a base.

The combination of the catalyst of formula IV and a suitable co-solventwas found to result high selectivity for the D incorporation in R⁴-R⁵over R¹-R³.

The deuterated ethanol (I) may be obtained by reacting the total amountof D₂O with ethanol in one step (as described above) or reacting D₂O inmultiple steps with a distillation step between the mixing steps (asdescribed as follows). Thus, in another aspect, the reacting step,comprises:

-   -   a. reacting a first portion of D₂O with ethanol,    -   b. collecting a distillate from the reacted mixture, and    -   c. adding a second portion of D₂O to the distillate to further        react unreacted ethanol with D₂O.

In another aspect, after step c), the process, further comprises:repeating steps b) and c) one or more times until the desired level of Dincorporation is achieved.

Accordingly, in another aspect, the reacting step, comprises:

-   -   a. reacting a first portion of D₂O with ethanol;    -   b. collecting a distillate from the reacted mixture;    -   c. adding a second portion of D₂O to the distillate to further        react with unreacted ethanol;    -   d. collecting a distillate from the reacted mixture; and,    -   e. adding a third portion of D₂O to the distillate to further        react with unreacted ethanol.

In another aspect, the reacting step, comprises:

-   -   a. reacting a first portion of D₂O with ethanol;    -   b. collecting a distillate from the reacted mixture;    -   c. adding a second portion of D₂O to the distillate to further        react with unreacted ethanol;    -   d. collecting a distillate from the reacted mixture;    -   e. adding a third portion of D₂O to the distillate to further        react with unreacted ethanol;    -   f. collecting a distillate from the reacted mixture; and    -   g. adding a fourth portion of D₂O to the distillate to further        react with unreacted ethanol.

When multiple steps are used, the amount of D₂O required for achievingthe desired D incorporation in ethanol is advantageously reducedcompared to the case where the total amount of D₂O is mixed with ethanolin one step. In step a), a first portion of D₂O is reacted with ethanolto obtain a partly reacted mixture with a certain degree of Dincorporation in ethanol. This partly reacted mixture also comprises H₂Oformed as a by-product of the D incorporation in ethanol, which inhibitsthe further D incorporation in ethanol. In step b), this partly reactedmixture is subjected to distillation to collect a distillate that mainlycomprises deuterated and non-deuterated ethanol. The distillatecomprises only a very small amount of H₂O. A second portion of D₂O isadded to the distillate, which allows further D incorporation.

In another aspect, the molar ratio of D₂O to ethanol mixed in thereacting step in each of the reaction sub-steps (a/c, a/c/e, a/c/e/g,etc.) is selected from 1, 2, 3, 4, and 5.

In another aspect, the reaction temperature is at most 200° C. Examplesof the reaction temperature include from 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140,145, 150, 155, 160, 165, 170, 175, to 180° C. Additional examplesinclude from 50-160° C. Further examples include from 50, 55, 60, 65,70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140,145, 150, 155, to 160° C.

In another aspect, the reaction is performed at a period of 0.5, 1, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95to 100 hours. Examples of the time the reaction is performed includefrom 1, 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70to 72 hours.

In another aspect, compound (I) can be separated from the reactionproduct by any ordinary post treatment operation for organic synthesis.Further, the crude product can be purified to a high purity, as needed,by standard methods including, activated carbon treatment, fractionaldistillation, recrystallization, and column chromatography. It can beconvenient to directly subject the completed reaction solution to adistillation recovery operation.

In the case where the reaction is performed in the presence of a base,the target compound of relatively high acidity tends to form a salt orcomplex with the base used and remain in the distillation residue duringdistillation recovery operation. In such a case, the target compound canbe obtained with high yield by neutralizing the reaction completedsolution with an organic acid (e.g., formic acid, acetic acid, citricacid, oxalic acid, benzoic acid, methanesulfonic acid orparatoluenesulfonic acid) or an inorganic acid (e.g., HCl, HBr, HNO₃,H₂SO₄) in advance, and then, subjecting the neutralized reactioncompleted solution to a distillation recovery operation (includingrecovery by washing the distillation residue with an organic solventsuch as diisopropyl ether).

It is noted that the invention relates to all possible combinations offeatures described herein. It will therefore be appreciated that allcombinations of features relating to the composition according to theinvention; all combinations of features relating to the processaccording to the invention and all combinations of features relating tothe composition according to the invention and features relating to theprocess according to the invention are described herein.

It should be understood that a description on a product/compositioncomprising certain components also discloses a product/compositionconsisting of these components. The product/composition consisting ofthese components may be advantageous in that it offers a simpler, moreeconomical process for the preparation of the product/composition.Similarly, it should be understood that a description on a processcomprising certain steps also discloses a process consisting of thesesteps. The process consisting of these steps may be advantageous in thatit offers a simpler, more economical process.

DEFINITIONS

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

When values are mentioned for a lower limit and an upper limit for aparameter, ranges made by the combinations of the values of the lowerlimit and the values of the upper limit are also understood to bedisclosed.

“Alkyl” includes the specified number of carbon atoms in a linear,branched, and cyclic (when the alkyl group has 3 or more carbons)configuration. Alkyl includes a lower alkyl groups (C₁, C₂, C₃, C₄, C₅,and C₆ or 1-6 carbon atoms). Alkyl also includes higher alkyl groups(>C₆ or 7 or more carbon atoms).

When an “ene” terminates a group it indicates the group is attached totwo other groups. For example, methylene refers to a —CH₂-moiety.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Substituted alkyl” is an alkyl group where one or more of the hydrogenatoms have been replaced with another chemical group (a substituent).Substituents include: halo, OH, OR (where R is a lower alkyl group),CF₃, OCF₃, NH₂, NHR (where R is a lower alkyl group), NR^(x)R^(y) (whereR^(x) and R^(y) are independently lower alkyl groups), CO₂H, CO₂R (whereR is a lower alkyl group), C(O)NH₂, C(O)NHR (where R is a lower alkylgroup), C(O)NR^(x)R^(y) (where R^(x) and R^(y) are independently loweralkyl groups), CN, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₂ aromatic ringgroup, substituted C₆₋₁₂ aromatic ring group, 5-12 membered aromaticheterocyclic group, and substituted 5-12 membered aromatic heterocyclicgroup.

Examples of the aromatic ring group are aromatic hydrocarbon groups astypified by phenyl, naphthyl and anthryl.

Examples of the aromatic heterocyclic group are aromatic hydrocarbongroups containing hetero atoms e.g. as nitrogen, oxygen or sulfur astypified by pyrrolyl (including nitrogen-protected form), pyridyl,furyl, thienyl, indolyl (including nitrogen-protected form), quinolyl,benzofuryl and benzothienyl.

“Substituted aromatic ring group” or “substituted aromatic heterocyclicring group” refers to an aromatic/aromatic heterocyclic ring group whereat least one of the hydrogen atoms has been replaced with anotherchemical group. Examples of such other chemical groups include: halo,OH, OCH₃, CF₃, OCF₃, NH₂, NHR (where R is a lower alkyl group),NR^(x)R^(y) (where R^(x) and R^(y) are independently lower alkylgroups), CO₂H, CO₂R (where R is a lower alkyl group), C(O)NH₂, C(O)NHR(where R is a lower alkyl group), C(O)NR^(x)R^(y) (where R^(x) and R^(y)are independently lower alkyl groups), CN, lower alkyl, aryl, andheteroaryl.

“Halo” refers to Cl, F, Br, or I.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The structures of catalyst (II) tested are as follows:

Experiments were performed by placing the catalyst (and the base whenrequired) inside a 5 mL vial under N₂ atmosphere. A mixture of ethanoland D₂O was added followed by the co-solvent when used. The vial wascapped and the temperature was increased to the desired reactiontemperature while stirring at 500 rpm with a magnetic stirred. After 16h, the reaction mixture was cooled. After purging with N₂, the autoclavewas opened and the reaction mixture was analyzed by ¹H NMR to determinethe D incorporation.

The abundance of D in the CH₂ position was determined by the amount ofthe residual H in the CH₂ position. The “residual H at the CH₂ position”was determined by the normalized ratio of area of the CH₂ signal in theethanol divided by the area of the CH₃ signal in the ethanol. Thecomplement to 100 of this quantity equals to the abundance of D in theCH₂ position.

Experiment Set 1

Ru-MACHO®-BH was tested without (Exp 1) and with various co-solvents(Exp 2-10). No base was used. The results are shown in Table 1.

TABLE 1 Cat amount Reaction Ratio 1 Rxn vol D inc. Exp (mmol) mixture(mmol) (mL) Ratio 2 T (°C.) time (h) at CH₂ 1 0.0053 — 2.21:15 0.5 400110 16 0 2 0.0206 d₈-THF 5.45:34 2 250 80 16 82 3 0.0089 d₈-Tol  4.1:712.2 462 80 21 92 4 0.0155 CPME 5.45:34 2 350 80 16 84 5 0.0162 Dioxane5.45:34 2 350 80 16 >98 6 0.0165 Diglyme 5.45:34 2 350 80 16 >98 70.0082 d₂-DCM  4.1:71 2.2 501 80 21 0 8 0.0082 d₃-CH₃CN  4.1:71 2.2 50180 21 0 9 0.0087 d₆-acetone  4.1:71 2.2 471 80 21 0 10 0.0157 tBuOH5.45:34 2 350 80 16 <5 11 0.0148 NMP 5.45:34 2 350 80 16 <5 Reactionmixture: all reaction mixtures contained EtOH:D₂O and the shownco-solvent. In all cases, the volume of the co-solvent was 1 mL. Ratio 1= ratio of EtOH:D₂O. Ratio 2 = mmolar ratio of EtOH:catalyst. DCM =dichloromethane. NMP = N-Methyl-2-pyrrolidone.

Experiment 1:

When no co-solvent was used, no D incorporation occurred at the desiredCH₂ position.

Experiments 2-6:

When a co-solvent of THF (tetrahydrofurane), toluene, CPME (cyclopentylmethyl ether), dioxane or diglyme was used, the catalyst dissolved inthe mixture of ethanol, D₂O and the co-solvent and D incorporationoccurred at the desired CH₂ position.

Experiments 7-11:

When a co-solvent of DCM (dichloromethane), CH₃CN, acetone, tBuOH, orNMP (N-Methyl-2-pyrrolidone) was used, little or no D-incorporationoccurred at the desired CH₂ position.

These results were not dependent on whether the co-solvent wasdeuterated or not.

Experiment Set 2

Ru-MACHO® was tested without (Exp 12) and with various co-solvents (Exp13-19).

TABLE 2 Cat amt Ratio 1 Rxn vol Ratio D inc. at Exp Catalyst additive(mmol) Rxn mix (mmol) (mL) 2 T (° C.) time (h) CH₂ 12 — 0.0071 2.21:150.5 300 110 16 0 13 HCO₂Na (55 eq/Ru) 0.0069 4.42:30 1 650 80 16 0 14NaHCO₃ (50 eq/Ru) 0.0102 4.42:30 1 450 80 16 0 15 NaBH₄ (14 eq/Ru)0.0160 5.45:34 1 350 80 16 0 16 — 0.0064 Tol 2.21:15 1 350 110 16 0 (0.5mL) 17 NaBH₄ (9 eq/Ru) 0.0058 Tol 2.21:15 1 400 110 16 85 (0.5 mL) 18NaBH₄ (5 eq/Ru) 0.0160 d₈-Tol 5.45:34 2 350 80 16 80 (1 mL) 19 NaBH₄ (7eq/Ru) 0.0160 Dioxane 5.45:34 2 350 80 16 75 (1 mL) Rxn Mix (Reactionmixture): all reaction mixtures contained EtOH:D₂O and the shownco-solvent. Ratio 1 = ratio of EtOH:D₂O. Ratio 2 = mmolar ratio ofEtOH:catalyst.

Experiments 12-15:

When no co-solvent was used, no D incorporation occurred at the desiredCH₂ position independent of the type of the base or the presence ofNaBH₄.

Experiment 16:

When no NaBH₄ was used, no D incorporation occurred at the desired CH₂position independent on the type of co-solvent.

Experiment 17-19:

The combination of a co-solvent and NaBH₄ resulted in D incorporation atthe desired CH₂ position.

Experiment Set 3

Various types of catalysts were tested in the absence of a co-solvent orin the presence of toluene. The results are shown in Table 3.

TABLE 3 Cat amt Ratio 1 Rxn vol Ratio D inc. Exp Catalyst (mmol) Rxn mix(mmol) (mL) 2 T (° C.) time (h) at CH₂ 20 Ru-MACHO-Cy 0.0054 2.21:15 0.5400 110 16 0 21 Ru-MACHO-Cy + NaBH4 0.0125 5.45:34 1 450 80 16 0 (14eq/Ru) 22 RuCl₂(PPh₃)₃ 2.57:71 150 150 30 min 0 60 min 0 23Ru(PPh₃)₃Cl₂ + NaBH₄ 0.0091 5.45:34 1 600 80 16 0 (18 eq/Ru) 24Ru(PPh₃)₃Cl₂ 0.0108 5.45:34 1 500 80 16 0 25 Ru(PPh₃)₃Cl₂ + AgOTf 0.00945.45:34 1 600 80 16 0 (5 eq/Ru) 26 Ru(Acac)₃ + TriPhos  1.7:118 104 15010 min 0 27 Ru(H)(BH₄)(dppp)(dpen) 0.0109 4.42:30 1 400 80 16 0 28Ru(H)(BH₄)(dppp)(dpen) 0.0100 Tol 4.42:30 2 450 80 16 0 (1 mL) 29Cp*Ir(BiPy)(OTf)2 0.0103 5.45:34 1 550 80 16 0 30 Cp*Ir(BiPy)(OTf)20.0100 Tol 5.45:34 2 550 80 16 0 (1 mL) 31 [Cp*IrCl₂]₂ 0.0095 5.45:34 1600 80 16 0 32 [Cp*IrCl₂]₂ + NaBH₄ 0.0080 5.45:34 1 700 80 16 0 (19eq/Ir) 33 [Cp*IrCl₂]₂ + AgOTf 0.0099 5.45:34 1 550 80 16 0 (3 eq/Ru) 34NaBH₄ 0.1900 5.45:34 1 30 80 16 12 Rxn Mix (Reaction mixture): allreaction mixtures contained EtOH:D₂O and the shown co-solvent. Ratio 1 =ratio of EtOH:D₂O. Ratio 2 = mmolar ratio of EtOH:catalyst.

Experiments 20-27, 29, and 31-34:

When no co-solvent was used, no or almost no D incorporation occurred atthe desired CH₂ position independent of the type of the catalyst.

Experiments 28 and 30:

When the catalyst was Ru(H)(BH₄)(dppp)(dpen) or Cp*Ir(BiPy)(OTf)₂, no Dincorporation occurred at the desired CH₂ position even in the presenceof a co-solvent.

Experiment Set 4

Various types of catalysts were tested in the presence of anon-deuterated toluene and THF. The results are shown in Table 4.

TABLE 4 Cat amt Rxn Ratio D inc. Exp Catalyst (mmol) Mix 2 at CH₂ 35Ru-MACHO ®-BH 0.0107 Tol 400 89 36 Ru-MACHO ®-BH 0.0121 THF 350 83 37Ru-MACHO-Cy + 20 eq NaBH₄ 0.0114 Tol 350 52 38 Ru-MACHO-Cy + 15 eq NaBH₄0.0125 THF 350 19 39 Ru-Firmenich + 25 eq NaBH₄ 0.0116 Tol 350 8 40Ru-Firmenich + 20 eq NaBH₄ 0.0117 THF 350 12 41 Ru-Noyori + 10 eq NaBH₄0.0182 Tol 200 6 42 Ru-Noyori + 15 eq NaBH₄ 0.0137 THF 300 5 43Ru(Cl)(H)(PPh₃)₃•Tol 0.0087 Tol 500 9 44 Ru(Cl)(H)(PPh₃)₃•Tol 0.0082 THF500 14 Rxn Mix (Reaction mixture): all reaction mixtures containedEtOH:D₂O and the shown co-solvent. Ratio 2 = mmolar ratio ofEtOH:catalyst. EtOH:D₂O ratio (mmol) 4.1:37.9 Reaction volume = 2 mL (1mL D₂O:EtOH, 1 mL co-solvent)

Experiments 35-36:

The use of a non-deuterated co-solvent in combination with Ru-MACHO®-BHresulted in D incorporation at the desired CH₂ position.

Experiments 37-44:

The use of a co-solvent with other catalysts resulted in insufficient Dincorporation at the desired CH₂ position.

Experiment Set 5

The influence of the molar ratio of D₂O:EtOH and the amount of theco-solvent on the degree of D incorporation was tested. In the followingexperiments, the molar ratio of D₂O to EtOH was 46 compared to about5-20 in Experiment set 1. The results are shown in Table 5.

TABLE 5 Cat amt Rxn Tol Ratio D inc. Exp Catalyst (mmol) Mix (vol) 2 atCH₂ 45 Ru-MACHO ® -BH 0.0107 Tol 1 95 97 46 Ru-MACHO ® -BH 0.0121 Tol0.5 84 97 47 Ru-MACHO ® -BH 0.0114 Tol 0.25 89 97 48 Ru-MACHO ® -BH0.0125 Tol 0.125 82 97 Rxn Mix (Reaction mixture): all reaction mixturescontained EtOH:D₂O and the shown co-solvent. Ratio 2 = mmolar ratio ofEtOH:catalyst. EtOH:D₂O ratio (mmol) = 1:46 Reaction volume = 1 mLD₂O:EtOH + various volume of Tol

The high molar ratio of D₂O:EtOH led to a very high D incorporation of97%. The same level of D incorporation was obtained for all experiments,even when only 12% vol/vol of Toluene was used. This can be advantageousfor increasing the loading of a reactor and therefore the productivity.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

What is claimed is:
 1. A process for the preparation of a deuterated ethanol of the formula (I) CR¹R²R³CR⁴R⁵OD   (I) comprising: reacting ethanol with D₂O in the presence of a ruthenium catalyst of formula (III) or (IV) and a co-solvent, provided that when the catalyst is of formula (III), the reaction is performed in the presence of an alkali metal borohydride:

whererin: R¹-R⁵ are independently H or D, provided that the abundance of D in R⁴ and R⁵ is at least 80% and the abundance of D in R¹-R³ is at most 25%; and, the co-solvent is selected from tetrahydrofuran, toluene, 1,4-dioxane, diglyme and cyclopentyl methyl ether.
 2. The process of claim 1, wherein the abundance of D in R⁴ and R⁵ is at least 90%.
 3. The process of claim 1, wherein the abundance of D in R⁴ and R⁵ is at least 90% and the abundance of D in R¹-R³ is at most 10%.
 4. The process of claim 1, wherein the catalyst is of formula (III).
 5. The process of claim 1, wherein the alkali metal borohydride is NaBH₄.
 6. The process of claim 1, wherein the catalyst is of formula (III) and the reaction is performed in the absence of NaOH.
 7. The process of claim 6, wherein the alkali metal borohydride is NaBH₄.
 8. The process of claim 1, wherein the catalyst is of formula (IV).
 9. The process of claim 1, wherein the catalyst is of formula (IV) and the reaction is performed in the absence of a base.
 10. The process of claim 1, wherein the reacting step comprises, a) reacting a first portion of D₂O with ethanol to form a reacted mixture; b) distilling the reacted mixture and collecting a distillate therefrom; and, c) adding a second portion of D₂O to the distillate to further react unreacted ethanol with D₂O.
 11. The process of claim 10, wherein the molar ratio of D₂O to ethanol mixed in each of the reaction sub-steps a) and c) is independently from 1-5.
 12. The process of claim 1, wherein the reacting step comprises, a) reacting a first portion of D₂O with ethanol to form a first reacted mixture; b) distilling the first reacted mixture and collecting a first distillate therefrom; c) adding a second portion of D₂O to the first distillate to further react with unreacted ethanol to form a second reacted mixture; d) distilling the second reacted mixture and collecting a second distillate therefrom; and, e) adding a third portion of D₂O to the second distillate to further react with unreacted ethanol.
 13. The process of claim 12, wherein the molar ratio of D₂O to ethanol mixed in each of the reaction sub-steps a), c), and e) is independently from 1-5.
 14. The process of claim 1, wherein the abundance of D in R⁴ and R⁵ is at least 95% and the abundance of D in R¹-R³ is at most 5%.
 15. The process of claim 1, wherein the abundance of D in R⁴ and R⁵ is at least 99.5% and the abundance of D in R¹-R³ is at most 1%.
 16. The process of claim 1, wherein the catalyst is of formula (IV) and the co-solvent is tetrahydrofuran.
 17. The process of claim 1, wherein the catalyst is of formula (IV) and the co-solvent is toluene.
 18. The process of claim 1, wherein the catalyst is of formula (IV) and the co-solvent is 1,4-dioxane.
 19. The process of claim 1, wherein the catalyst is of formula (IV) and the co-solvent is diglyme.
 20. The process of claim 1, wherein the catalyst is of formula (IV) and the co-solvent is cyclopentyl methyl ether.
 21. The process of claim 1, wherein the catalyst is of formula (III), the base is NaBH₄ and the co-solvent is toluene.
 22. The process of claim 1, wherein the catalyst is of formula (III), the base is NaBH₄ and the co-solvent is 1,4-dioxane.
 23. The process of claim 1, wherein the catalyst is of formula (III), the base is NaBH₄ and the co-solvent is diglyme.
 24. The process of claim 1, wherein the catalyst is of formula (III), the base is NaBH₄ and the co-solvent is cyclopentyl methyl ether. 